Journal Article

Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are immunopathogenic upon gastrointestinal norovirus infection

Sarvestani, Soroush T., Wullaert, Andy, Sorgeloos, Frederic, Saeys, Yvan, Mackenzie, Jason M., van Loo, Geert, Martens, Liesbet, Dubois, Hanne, Goodfellow, Ian, Lamkanfi, Mohamed

2019

Overview

Norovirus infection is the leading cause of food-borne gastroenteritis worldwide, being responsible for over 200,000 deaths annually. Studies with murine norovirus (MNV) showed that protective STAT1 signaling controls viral replication and pathogenesis, but the immune mechanisms that noroviruses exploit to induce pathology are elusive. Here, we show that gastrointestinal MNV infection leads to widespread IL-1β maturation in MNV-susceptible STAT1-deficient mice. MNV activates the canonical Nlrp3 inflammasome in macrophages, leading to maturation of IL-1β and to Gasdermin D (GSDMD)-dependent pyroptosis. STAT1-deficient macrophages displayed increased MAVS-mediated expression of pro-IL-1β, facilitating elevated Nlrp3-dependent release of mature IL-1β upon MNV infection. Accordingly, MNV-infected Stat1-/- mice showed Nlrp3-dependent maturation of IL-1β as well as Nlrp3-dependent pyroptosis as assessed by in vivo cleavage of GSDMD to its active N-terminal fragment. While MNV-induced diarrheic responses were not affected, Stat1-/- mice additionally lacking either Nlrp3 or GSDMD displayed lower levels of the fecal inflammatory marker Lipocalin-2 as well as delayed lethality after gastrointestinal MNV infection. Together, these results uncover new insights into the mechanisms of norovirus-induced inflammation and cell death, thereby revealing Nlrp3 inflammasome activation and ensuing GSDMD-driven pyroptosis as contributors to MNV-induced immunopathology in susceptible STAT1-deficient mice.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Animals / Apoptosis / Apoptosis Regulatory Proteins - genetics / Apoptosis Regulatory Proteins - metabolism / Applied mathematics / Biology and Life Sciences / Caliciviridae Infections - immunology / Caliciviridae Infections - metabolism / Caliciviridae Infections - pathology / Caliciviridae Infections - virology / Cell death / Cells, Cultured / Computer science / Cytokines / Funding / Gastroenteritis / Gastrointestinal diseases / Gastrointestinal Tract - immunology / Gastrointestinal Tract - metabolism / Gastrointestinal Tract - pathology / Gastrointestinal Tract - virology / IL-1β / Immune response / Immunology / Infection / Infections / Inflammasomes / Inflammasomes - immunology / Inflammasomes - metabolism / Inflammation / Influenza / Interleukin-1beta - metabolism / Internal medicine / Intracellular Signaling Peptides and Proteins / Lethality / Lipocalin / Macrophages / Macrophages - immunology / Macrophages - metabolism / Macrophages - pathology / Macrophages - virology / Maturation / Medicine and Health Sciences / Mice / Mice, Inbred C57BL / Mice, Knockout / Molecular biology / Murinae / NLR Family, Pyrin Domain-Containing 3 Protein - genetics / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / Norovirus / Norovirus - immunology / Norovirus - pathogenicity / Pathogenesis / Pathology / Pediatrics / Phosphate-Binding Proteins / Physiological aspects / Prevention / Pyroptosis / Pyroptosis - physiology / Risk factors / RNA polymerase / Stat1 protein / STAT1 Transcription Factor - physiology / Supervision / Viral infections / Virology / Virus replication / West Nile virus